TUMOR MUTATIONAL burden is emerging as a predictive biomarker for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in non–small cell lung cancer (NSCLC), as well as other tumor types. However, experts say tumor mutational burden has hurdles to overcome. At the 2018 Annual Meeting of the American Association for Cancer Research (AACR), an updated analysis of the CheckMate 568 trial showed that tumor mutational burden ≥ 10 mut/mb distinguished responders from nonresponders to nivolumab plus ipilimumab, and patients with high tumor mutational burden predicted response, irrespective of programmed cell death ligand 1 (PD-L1) level.¹ 

Suresh Ramalingam, MD

“Tumor mutational burden was an informative classifier of response with nivolumab and ipilimumab in patients with PD-L1 < 1% and PD-L1 ≥ 1%. Both PD-L1 and tumor mutational burden are independent and distinct biomarkers,” said lead author Suresh Ramalingam, MD, of Emory University’s Winship Cancer Institute, Atlanta. 

Efforts to identify a valid biomarker for response to immunotherapy have been disappointing thus far. PD-L1 expression on its own is problematic, since both PD-L1–positive and PD-L1–negative NSCLC tumors respond to anti–programmed cell death protein 1 (anti–PD-1) and anti–PD-L1 checkpoint inhibitors. 

A previous study in the CheckMate program, CheckMate 012, suggested that tumor mutational burden could identify patients who benefit from the nivolumab/ipilimumab combination.² The study showed durable activity for the combination and identified optimized dosing, which was brought forward in CheckMate 568. In that trial, PD-L1 expression was not clearly associated with response. 

CheckMate 568 Details 

CHECKMATE 568 is a large phase II trial that evaluated first-line therapy with nivolumab/ipilimumab in 288 patients with advanced NSCLC. Patients received optimized dosing of nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks and were treated until disease progression, toxicity, or a maximum of 2 years. 

The main objectives of CheckMate 568 were to determine the efficacy of the combination regimen and to determine biomarkers for patient selection. Selected secondary endpoints were progression-free and overall survival stratified by tumor mutational burden. The investigators used a next-generation sequencing assay to detect substitutions, insertions, deletions, and copy number alterations in 324 genes by using the FoundationOne CDX assay. 

Samples were obtained from all patients. Of the 288 patients enrolled in the trial, 252 were evaluable for PD-L1 expression; 120 patients were evaluable for tumor mutational burden; and 95 were evaluable for both. At baseline, demographic and disease characteristics were comparable in both PD-L1–positive and tumor mutational burden–positive patients. Among tumor mutational burden–evaluable patients, 49% were tumor mutational burden–positive, using a cutoff point of tumor mutational burden ≥ 10 mut/mb. 

“This is comparable to other NSCLC data sets,” Dr. Ramalingam told the audience. “We found no clear association between tumor mutational burden and PD-L1 expression.” 

The overall response rate was 30%. In PD-1–evaluable patients, the overall response rate was 29%, and in tumor mutational burden–evaluable patients, it was 28%. The overall response rate was 41% for high– PD-L1 patients (ie, > 1%) vs 15% for low–PD-L1 patients (< 1%). For a tumor mutational burden < 5 mut/mb, the overall response rate was 9%; for a tumor mutational burden of between 5 and 10 mut/mb, it was 15%; for a tumor mutational burden ≥ 10 mut/mb, it was 44%; and for a tumor mutational burden > 15 mut/mb, it was 39%. The investigators deemed a tumor mutational burden > 10 mut/mb as the optimal cutoff point. 

For patients with a high tumor mutational burden, 6-month progression-free survival was 55%, vs 31% for those with a low tumor mutational burden. Median progression-free survival was 7.1 months vs 2.6 months, respectively. 

Treatment-emergent adverse events of any grade were experienced by 80% of patients; grades 3 to 4 adverse events were reported in 29%. The most common adverse events were fatigue, diarrhea, pruritus, and nausea. ■

DISCLOSURE: Dr. Ramalingam has served on advisory boards for and received honoraria from BMS, Merck, Genentech/Roche, AstraZeneca, Amgen, Lilly, Loxo Oncology, and Nektar. 

REFERENCES 

1. Ramalingam S, et al: Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab + ipilimumab in first-line, non-small cell lung cancer. 2018 AACR Annual Meeting. Abstract CT078. Presented April 16, 2018. 

2. Hellmann MD, et al: Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012). Lancet Oncol 18:31-41, 2017.